-
`I
`
`1990
`
`USP XXII
`
`NF XVII
`
`THE UNITED ST ATES PHARMACOPEIA
`THE NATIONAL FoRMULARY
`
`By authority of the United States Pharmacopeial
`Convention, Inc., meeting at Washington,
`D.C. ,
`March 22-24, 1985. Prepared
`by the Committee of
`the Board of Trustees
`Revision and published by
`
`Official from January 1, 1990
`
`UNITED STATES PHARMACOPEIAL CONVENTION, INC.
`12601 Twinbrook
`Parkway,
`Rockville,
`MD 20852
`
`-
`_-----, - .. --- -- --■
`
` PFIZER, INC. v. NOVO NORDISK A/S - IPR2020-01252, Ex. 1068, p. 1 of 158
`
`

`

`NOTICE AND WARNING
`
`
`
`Rights Concerning U. S. Patent or Trademark
`
`
`
`The inclusion in the Pharmacopeia or in the National Formulary of a monograph on any
`
`
`
`
`
`drug in respect to which patent or trademark rights may exist shall not be deemed, and is
`
`
`
`
`
`
`not intended as, a grant of, or authority to exercise, any right or privilege protected by such
`
`
`patent or trademark. All such rights and privileges are vested in the patent or trademark
`
`
`
`
`
`owner, and no other person may exercise the same without express permission, authority, or
`
`
`
`license secured from such patent or trademark owner.
`
`Concerning Use of USP or NF Text
`
`Attention is called to the fact that USP and NF text is fully copyrighted. Authors and
`
`
`
`
`
`
`others wishing to use portions of the text should request permission to do so from the
`
`Secretary of the USPC Board of Trustees.
`
`© 1989 The United States Pharmacopeial Convention,
`Inc.
`12601 Twinbrook Parkway,
`
`Rockville, MD 20852
`
`All rights reserved
`
`
`
`ISSN 0195-7996
`
`ISBN 0-913595-37-3 (cloth)
`
`0-913595-38-l (leather)
`
`Library of Congress Catalog Card Number 83-640088
`
`
`
`
`
`
`
`Printed by Mack Printing Company, Easton, PA 18042
`
` PFIZER, INC. v. NOVO NORDISK A/S - IPR2020-01252, Ex. 1068, p. 2 of 158
`
`

`

`Guide to GENERAL CHAPTERS
`
`(For complete alphabetic list of all general chapters in this Pharmacopeia, see under “General chapters” in the index.)
`
`General Tests and AsSays
`
`General Requirements for Tests and Assays
`(l) Injections .
`. . 1470
`(ll) USP Reference Standards .
`
`1472
`
`Apparatus for Tests and Assays
`(16) Automated Methods of Analysis . .
`. 1473
`(21) Thermometers .
`.
`. 1477
`(31) Volumetric Apparatus . .
`(41) Weights and Balances
`.
`_
`_
`Microbiological Tests
`.
`-
`-
`-
`-
`(51) Antirmcroblal Presermoves—Effectiveness .
`(61) Microbial Limit Tests . .. 1479
`(71) 5“”th Tm "' 1483
`
`. 1477
`1477
`
`.
`
`. 1478
`
`Biological Tests and Assays
`(81) Antibiotics—Microbial Assays .
`.
`. 1488
`(85) Bacterial Endotoxins Test . . . 1493
`(87) Biological Reactivity Tests, In<vitro . .
`. 1495
`(88) Biological Reactivity Tests, In-V1V0 . . . 1497
`<91) Calcium Pantothenate Assay '
`' ‘ 1500
`(101) Depressor Substances Test .
`.
`. 1502
`(111) Design and Analysis of Biological Assays .
`(115) Dex anthenol Assay .
`.
`. 1512
`(121)
`Insu in Assay... 1513
`(141) Protein—Biological Adequacy Test . . . 1514
`(I51) Pyrogen Test '
`'
`- 1515
`(161) Transfusion and Infusion Assemblies . .
`. 1516
`(171) Vitamin 312 Activity Assay .
`. . 1516
`
`.
`
`. 1502
`
`Chemical Tests and Assays
`
`.
`
`. 1518
`
`IDENTIFICATION TESTS
`Identification—Organic Nitrogenous Bases .
`(181)
`Identification Tests—General .
`.
`. 1.518
`(191)
`.
`Identification—Tetracyclines .
`. 1520
`(193)
`(201) Thin-layer Chromatographic Identification Test . . . 1520
`T
`LIMIT TES S
`_
`(211) M5991“ - - - 1529
`(216) Calc1um, Potassmm, and Sodium . .
`(221) Chloride and Sulfate .
`. . 1522
`_
`1224) D103?“ -
`- - I522
`(226) 4-Ep1anhydrotetracychne .
`(231) Heavy Metals .
`.
`. 1523
`(241)
`Iron - -- 1524
`(251) Lead --- 1525
`(251) WWW - -- 15.26
`(271) Rea'dlly Carbonizable Substances Test
`(281) Res1d_ue on Igrution . .
`. 1527
`(291) Selenium -
`-
`- 1527
`1468
`
`. 1522
`
`. . 1523
`
`. . 1527
`
`. . 1529
`
`OTHER TESTS AND ASSAYS
`
`(301) Acid-neutralizing Capacity . . . 1528
`(311) Alginates Assay .
`.
`. 1528
`(fig glkagoidal DrugsAssays; Il’gglgmat'e Assays .
`t
`.
`.
`.
`(341) Aiiiijmicigiigi Aggie—Content . .. 1530
`(351) A553)! for StGTOIdsx- -
`- 1532
`(361) Barbltu ate Assay .
`.
`. 1532
`(371) Cobal m Radiotracer Assay
`1533
`8%; Elasto hereirzc glfsures fOIt‘sialflectlons . .. 1533
`
`p
`p
`he
`say . . .
`(401) Fats\_and Fixed Oils . .. 1535
`(411; Folic Acid Assay... 1536
`1 H drox
`ro ox Determination .
`.
`. 1537
`(42
`y
`y}? P y
`.
`.
`.
`(2%?)
`fidOfimmlgAssaX—Amlbmnfgjé- I 33
`,
`run
`I
`. .
`. 1.;
`(4412 Nigeria? Pifgiiiziiiiidgnidissay
`"39
`(451) Nitrite Titration .
`.
`. 1541
`(23;) gigogcn lgctenzlilnafion 1.52:; 542
`2468; 0;yg':;ggglgfigggdfi-
`1543
`(471) oxygen Flask Combustion
`1543
`(475) Penicillin G Determination. ' ' 1544
`(481) Riboflavin Assay
`1544 I . ‘
`(501) Salts of Organic Nitrogenous Bases
`(51] ) Single-steroid Assay
`1545
`(521) Sulfonamides
`1545"
`(531) Thiamine Assay I
`1546
`(541) Titrimetry...1547
`. 1549
`.
`(55]) Alpha Tocopherol Assay ’
`(561) Vegetable Drugs—Sampling and Methods
`of Analysis
`1549
`(571) Vitamin A Assay.
`_ 1550
`(581) Vitamin D Assay... 1551
`(591) Zinc Deterrrunatlon .
`.
`. 1555
`
`'
`
`' '
`
`1544
`
`1557
`
`Physical Tests and Determinations
`(601) Aerosols
`1556
`(611) A1001'101 betermination
`(621) Chromatography
`1558
`_ 1568
`(631) Color and Achromicity .
`.
`(64]; Complelteness of Solution .
`. . 1569
`. . 1569
`(651 Congea ing Temperature .
`(661) Containers . .. 1570'
`(671) Containers—Permeation . .. 1575
`(691) Cotton _ .
`. 1576
`(695) Crystallinity _ .. 1577
`(701) Dishltegration . .. 1577
`(711) Dissolution... 1578
`(721) Distilling Range .
`.
`_ 1579
`(724) Drug Release. .. 1580
`(726) Electrophoresis . .. 1583
`(731) Loss on Drying... 1586
`(733) Loss on Ignition _
`.
`~ 1586
`(736) Mass Spectrometry . . . 1586
`(741) Melting Range 01' Temperature . . 1588
`
`
`
` PFIZER, INC. v. NOVO NORDISK A/S - IPR2020-01252, Ex. 1068, p. 3 of 158
`
`

`

`USP XXII
`
`:-
`
`(751) Metal Particles in Ophthalmic Ointments .
`(755) Minimum Fill
`1589
`(761) Nuclear Magnetic Resonance .
`(771)
`Ophthalmic Ointments .
`.
`. 1594
`(781)
`Optical Rotation .
`.
`. 1595
`(785)
`Osmolarity . . . 1595
`(788)
`Particulate Matter in Injections
`(791)
`pH . . . 1598
`(801)
`Polarography . . . 1599
`(811)
`Powder Flneness .
`.
`. 1602
`(821)
`Radioactivity... 1602
`Refractive Index .
`. . 1609
`(831)
`
`. 1590
`
`.. 1596
`
`.
`
`. 1589
`
`Guide to General Chapters
`
`1469
`
`(841)
`(851)
`(861)
`(871)
`(881)
`(891)
`(901)
`(905)
`(911)
`(921)
`(941)
`
`. . 1609
`Specific Gravity .
`Spectrophotometry and Light-scattering . . . 1609
`Sutures—Diameter . .
`. 1614
`Sutures—Needle Attachment .
`. . 1614
`Tensile Strength .
`.
`.‘ 1615
`Thermal Analysis . .
`. 1615
`Ultraviolet Absorbance of Citrus Oils . .
`Uniformity of Dosage Units .
`.
`. I617
`Viscosity... 1619
`. 1619
`Water Determination
`X-ray Diffraction .
`.
`. 1621
`
`. 1617
`
`General Information
`
`(1001)
`(1035)
`(1041)
`(1051)
`(1061)
`(1071)
`(1076)
`
`(1077)
`
`(1081)
`(1086)
`(1091)
`(1101)
`(1111)
`
`. 1624
`Antacid Effectiveness . .
`Biological Indicators .
`.
`. 1625
`Biologics .
`. . 1627
`. . 1627
`Cleaning Glass Apparatus .
`. 1627
`Color—Instrumental Measurement . .
`Controlled Substances Act Regulations .
`. . 1629
`Federal Food, Drug, and Cosmetic Act Requirements
`Relating to Drugs for Human Use .
`.
`. 1655
`Good Manufacturing Practice for Finished
`Pharmaceuticals . . . 1671
`Gel Strength of Gelatin . . . 1682
`_
`Im urities in Official Articles . . . 1682
`Lageling of Inactive Ingredients .
`.
`. 1684
`Medicine Dropper .
`.
`. I684
`Microbiological Attributes of Nonsterile
`Pharmaceutical Products . .1 I684
`
`v
`
`(1121)
`(1141)
`(1151)
`(1171)
`(1176)
`
`(118])
`(1191)
`
`(1211)
`
`(1221)
`(1225)
`(1231)
`(1241)
`
`1685
`Nomenclature .
`. 1685
`.
`Packaging~Child-safety .
`Pharmaceutical Dosage Forms .
`.
`. 1688
`Phase-solubility Analysis .. . 1697
`Prescription Balances and Volumetric
`Apparatus... 1699
`Scanmng Electron Microscopy . . . 1700
`Stability Considerations in Dispensing
`Practice... 1703
`Sterilization and Sterility Assurance of Compendial
`Articles .
`.
`. 1705
`Teas oon
`1710
`. 1710
`Vali ation of Compendial Methods .
`. . 1712
`Water for Pharmaceutical Purposes .
`Water-solid Interactions in Pharmaceutical
`Systems... 1713
`
`.
`
`
`
`
`
`
`
`
`
` PFIZER, INC. v. NOVO NORDISK A/S - IPR2020-01252, Ex. 1068, p. 4 of 158
`
`

`

`GENERAL CHAPTERS
`
`General Tests
`
`and Assays
`
`General Requirements
`for Tests and Assays
`
`(l)
`
`INJECTIONS
`
`rod-
`Every care should be exercised in the preparation of all
`ucts intended for injection, to prevent contamination wit mi-
`croorganisms and foreign material. Good pharmaceutical prac-
`tice requires also that each final container of Injection be subjected
`individually to a physical inspection, whenever the nature of the
`container permits, and that every container whose contents show
`evideéice of contamination with visible foreign material be re-
`jecte .
`Definitions—In this Pharmacopeia, the sterile preparations for
`parenteral use are grouped into five distinct classes, defined as
`follows: (1) medicaments or solutions or emulsions thereof suit-
`able for injection, bearing titles of the form, _ Injection; (2)
`dry solids or liquid concentrates containing no buffers, diluents,
`or other added substances, and which, upon the addition of suit-
`able solvents, yield solutions conforming in all respects to the
`requirements for Injections, and which are distinguished by titles
`of the form, Sterile _; (3) preparations the same as those
`described under (2) except that they contain one or more buffers,
`diluents, or other added substances, and which are distinguished
`by titles of the form, _ for Injection; (4) solids which are
`suspended in a suitable fluid medium and which are not to be
`injected intravenously or into the spinal canal, distinguished by
`titles of the form, Sterile _ Suspension; and (5) dry solids,
`which, upon the addition of suitable vehicles, yield preparations
`conforming in all respects to the requirements for Sterile Sus-
`pensions, and which are distinguished by titles of the form, Sterile
`__ for Suspension.
`A Pharmacy bulk package is a container of a sterile prepa-
`ration for parenteral use that contains many single doses. The
`contents are intended for use in a pharmacy admixture program
`and are restricted to the pre aration of admixtures for infusion
`or, through a sterile transfer evice, for the filling of empty sterile
`syringes.
`_The closure shall be penetrated only one time after constitution
`With a suitable sterile transfer device or dispensing set which
`allows measured dispensing of the contents. The Pharmac bulk
`package is to he used only in a suitable work area suc
`as a
`1/17!)
`
`
`laminar flow hood (or an equivalent clean air compounding area).
`Designation as a Pharmacy bulk package is limited to prep-
`arations from classes 1, 2, or 3 as defined abbve. Pharmacy bulk
`packages, although containing more than one single dose, are
`exempt from the multiple-dose container volume limit of 30 mL
`and the requirement that they contain a substance or suitable
`mixture of substances to prevent the growth of microorganisms.
`Where a container is offered as a Pharmacy bulk package, the
`label shall (a) state prominently “Pharmacy Bulk Package—Not
`for direct infusion,” (b) contain or refer to information on roper
`techniques to help assure safe use of the product, and (c bear
`a statement limiting the time frame in which the container may
`be used once it has been entered, provided it is held under the
`labeled storage conditions.
`Where used in this Pharmacopeia, the designation Large-vol-
`ume intravenous solution applies to a single-dose injection_that
`is intended for intravenous use and is packaged in containers
`labeled as containing more than 100 mL. The designation Small-
`valume Injection applies to an Injection that is packaged in con-
`tainers labeled as containing 100 mL or less.
`The Pharmacopeial definitions for sterile preparations‘for par-
`enteral use generally do not apply in the case of the biologics,
`because of their special nature and licensing requirements (see
`Biologics (1041)).
`Aqueous Vehicles—The vehicles for aqueous Injections meet
`the requirements of the Pyrogen Test (151) or the Bacterial
`Endotoxins Test (85), whichever is specified. Water for by?"
`tion generall
`is used as the vehicle, unless otherwise spectfled
`in the indivi ual monograph. Sodium chloride may be added In
`amounts sufficient to ren er the resulting solution isotonic; and
`Sodium Chloride Injection, or Ringer‘s Injection, may be used
`in whole or in part instead of Waterfor Injection unless otherwise
`specified in the individual monograph. For conditions applying
`to other adjuvants, see Added Substances, in this chapter.
`Other Vehicles—Fixed oils used as vehicles for nona‘lueous
`injections are of vegetable origin, are odorless or nearly 50! and
`have no odor or taste suggesting rancidity. ”they meet the 1'9-
`quirements of the. test for Solid paraffin under Mineral Oil, the
`cooling bath being maintained at 10°, have a Sapomficatmn value
`of between 185 and 200 (see Fats and Fixed Oils (409% hays
`an Iodine value of between 79 and 128 (see Fats and Fixed 0‘15
`(401)), and meet the requirements of the following tests:
`Unsaponiflable Matter—Reflux on a steam bath 10 mL offill:
`oil with 15 mL of sodium hydroxide solution (1 in 6) and 30
`.
`.
`of alcohol, with occasional shaldng until the mixture becomt‘is
`clear. Transfer the solution to a shallow dish, evaporate the 8"
`coho] on a steam bath, and mix the residue with 100 mL of water:
`a clear solution results.
`
`N'I'l-QI-u—A
`
`
` PFIZER, INC. v. NOVO NORDISK A/S - IPR2020-01252, Ex. 1068, p. 5 of 158
`
`

`

`USP XXII
`
`Free Fatty Acidsh'lhe free fatty acids in 10 g of oil require
`for neutralization not more than 2.0 mL of 0.020 N sodium hy-
`droxide (see Fats and Fixed Oils (401)).
`Synthetic mono- or diglycerides of fatty acids may be used as
`vehicles, provided they are liquid and remain clear when cooled
`to 10° and have an Iodine value of not more than 140 (sec Fats
`and Fixed Oils (401)).
`These and other nonaqueous vehicles may be used, provided
`they are safe in the volume of injection administered, and also
`provided they do not interfere with the therapeutic efficacy of
`the preparation or with its response to prescribed assays and tests.
`Added Substances—Suitable substances may be added to in-
`crease stability or usefulness, unless proscribed in the individual
`monograph,
`rovided they are harmless in the amounts admin-
`istered and 0 not interfere with the therapeutic efficacy or with
`the responses to the specified assays and tests. No coloring agent
`may be added, solely for the purpose of coloring the finished
`reparation, to a solution intended for parenteral administration
`see also Added Substances under General Notices, and Anti-
`microbial Preservatives—Ejjfectiveness (5 1 )).
`Observe special care in the choice and use of added substances
`in preparations for injection that are administered in a volume
`exceeding 5 mL. The following maximum limits prevail unless
`otherwise directed: for agents containing mercury and the cat-
`ionic, surface-active compounds, 0.01%; for those of the types of
`chlorobutanol, cresol, and phenol, 0.5%; and for sulfur dioxide,
`or an equivalent amount of the sulfite, bisulfite, or metabisulfite
`of potassium or sodium, 0.2%.
`‘A suitable substance or mixture of substances to prevent the
`growth of microorganisms must be added to preparations in-
`tended for in'ection that are packaged in multiple-dose con-
`tainers, regar less of the method of sterilization employed, unless
`otherwise directed in the individual monograph, or unless the
`active ingredients are themselves antimicrobial. Such substances
`are used in Concentrations that will prevent the growth of or kill
`microorganisms in the preparations for injection (see also Anti-
`microbial Preservatives—Effectiveness (51) and Antimicrobial
`Agents—Content (341)). Sterilization processes are employed
`even though such substances are used (see 91150 Parenteral and
`Topical Preparations in the section, Added Substances, under
`General Notices, and Sterilization and Sterility Assurance of
`Compendial Articles (1211)). The air in the container may be
`evacuated or be displaced by a chemically inert gas.
`Containers for Injections—Containers, including the closures,
`for preparations for injection do not interact physically or chem-
`ically with the preparations in any manner to alter the strength,
`quality, or purity beyond the'official re uirements under the or-
`dinary or mistomary conditions of han 'ng, shipment, storage,
`sale, and use. The container is made of material that permits
`inspection of the contents. The type of glass preferable for each
`parcEteral preparation is usually stated in the individual mono-
`grap .
`For definitions of single-dose and multiple-dose containers, see
`Containers under General Notices. Containers meet the require-
`ments under Containers (661).
`Containers are closed by fusion, or by application of suitable
`closures, in such manner as to prevent contamination or loss of
`contents. Closures for multiple—dose containers permit the with-
`drawal'of the contents without removal or destruction of the
`closure. The closure permits penetration by a needle, and, upon
`withdrawal of the needle, at once recloses the container against
`contamination.
`
`Containers for Sterile Solids—Containers, including the clo-
`sures, for dry solids intended for parenteral use do not interact
`physically or chemically with the preparation in any manner to
`alter the strength, quality, or purity beyond the official require-
`ments under the ordinary or customary conditions of handling,
`shipment, storage, sale, and use.
`.
`A container for a sterile solid permits the addition of a suitable
`solvent and withdrawal of portions of the resulting solution or
`suspension in such manner that the sterility of the product is
`maintained.
`‘
`.
`Where the Assay in a monograph provides a procedure for
`4ssay preparation in which the total withdrawable contents are
`to be withdrawn from a single-dose container with a hypodermic
`needle and syringe, the contents are to be withdrawn as com-
`pletely as possible into a dry hypodermic syringe of a rated ca-
`pacity not exceeding three times the volume to be withdrawn and
`
`General Requirements / Injections
`
`(1)
`
`1471
`
`fitted with a 21—gauge needle not less than 2.5 cm (1 inch) in
`length, care being taken to expel any air bubbles, and discharged
`into a container for dilution and assay.
`Volume in Container—Each container of an Injection is filled
`with a volume in slight excess of the labeled “size” or that volume
`which is to be withdrawn. The excess volumes recommended in
`the accompanying table are usually sufficient to permit with-
`drawal an administration of the labeled volumes.
`DETERMINATION OF VOLUME 0F INJECTION IN CON-
`TAINERS—Select 1 or more containers if the volume is 10 mL
`or more, 3 or more if the volume is more than 3 mL and less
`than 10 mL, or 5 or more if the volume is 3 mL or less. Take
`up individually the contents of each container selected into a dry
`hypodermic syringe of a rated ca acity not exceeding three times
`the volume to be measured, an fitted with a 21-gauge needle
`not less than 2.5 cm (1 inch) in length. Expel any air bubbles
`from the syringe and needle, and then discharge the contents
`of the syringe, without emptying the needle, into a standardized,
`dry cylinder (graduated to contain rather than to deliver the
`designated volumes) of such size that the volume to be measured
`occupies at least 40% of its rated volume. Alternatively, the
`contents of the syringe may be discharged into a dry, tared beaker,
`the volume, in mL, being calculated as the weight, in g, of In-
`jection taken divided by its density. The contents of two or three
`l-mL or 2-rnL containers may be pooled for the measurement,
`provided that a separate, dry syringe assembly is used for each
`container. The content of containers holding 10 mL or more may
`be determined by means of opening them and emptying the con-
`tents directly into the graduated cylinder or tared beaker.
`
`Recommended Excess Volume
`For Mobile
`For Viscous
`Labeled Size
`Li uids
`Li uids
`0.5 mL
`0.10 mL
`0.12 mL
`1.0 mL
`0.10 mL
`015 mL
`2.0 ml.
`0.15 mL
`U 25 ml
`5.0 mL
`0.30 mL
`0.50 mL
`10.0 mL
`0.50 mL
`0.70 mL
`20.0 mL
`0.60 mL
`0.90 mL
`30.0 mL
`0.80 mL
`1.20 ml.
`50.0 mL
`
`or more 3% 2%
`
`
`
`The volume is not less than the labeled volume in the case of
`containers examined individually or, in the case of Hut. and 2-
`mL containers, is not less than the sum of the labeled volumes
`of the containers taken collectively.
`For Injections in multipledose containers labeled to yield a
`specific number of doses of a stated volume, proceed as directed
`in the foregoing, using the same number of separate syringes as
`the number of doses specified. The volume is such that each
`syringe delivers not less than the stated dose.
`For Injections containing oil. warm the containers, if necessary,
`and thoroughl
`shake them immediately before removing the
`contents. Coo to 25" before measuring the volume,
`Particulate Matter—All large-volume Injections for single-dose
`infusion, and those small-volume Injections for which the mono-
`graphs specify such requirements, are subject to the particulate
`matter limits set forth under Particulate Matter in Injections
`(788). An article packaged as both a large-volume and a small-
`volume Injection meets the requirements set forth for Small-
`volume Injections where the container 18 labeled as containing
`100 mL or less if the individual monograph includes a test for
`Particulate matter: it meets the requirements set forth for Large-
`volume Injections for Single-dose Infusion where the container
`is labeled as containing more than 100 mL. Injections packaged
`and labeled for use. as irrigating solutions are exempt from re-
`quirements for Particulate matter.
`Sterility Tests—Preparations for injection meet the require-
`ments under Sterility Tests (71).
`Labeling——[NOTE—See definitions of “label" and “labeling”
`under Preservation, Packafiing, Storage, and Labeling—Label-
`ing in the General Notices.
`The label states the name of the preparation; in the case of a
`liquid preparation, the percentage content of drug or amount of
`drug in a specified volume; in the case of a dry preparation, the
`
`
`
`
`
` PFIZER, INC. v. NOVO NORDISK A/S - IPR2020-01252, Ex. 1068, p. 6 of 158
`
`

`

`P
`
`1472
`
`(ll) USP Reference Standards / General Requirements
`
`USP XXII
`
`amount of active ingredient; the route of administration; a state-
`ment of storage conditions and an expiration date; the name of
`the manufacturer and distributor; and an identifying lot number.
`The lot number is capable of yielding the complete manufacturing
`history of the specific package, including all manufacturing, fill-
`ing, sterilizing, and labeling operations.
`Where the individual monograph permits varying concentra-
`tions of active ingredients in the large-volume parenteral, the
`concentration of each ingredient named in the official title is
`stated as if part of the official title, e.g., Dextrose Injection 5%,
`or Dextrose (5%) and SodiumChloride (0.2%) Injection.
`The labeling includes the following information, if the complete
`formula is not specified in the individual monograph: (1) In' the
`case of a liquid preparation, the percentage content of each in-
`gredient or the amountof each ingredient in a specified volume,
`except that ingredients added to adjust to a given pH or to make
`the solution isotonic may be declared by name and a statement
`of their effect; and (2),in the case of a dry preparation or other
`preparation to which a diluent is intended to be added before
`use, the amount of each ingredient, the composition of recom-
`mended diluent(s) [the name(s) alone, if the formula is specified
`in the individual monograph], the amount to be used to attain a
`specific concentration of active ingredient and the final volume
`of solution so obtained, a brief description of the physical ap-
`pearance of the constituted solution, directions for proper storage
`of the constituted solution, and an expiration date limiting the
`period during which the constituted solution may be expected to
`have the required or labeled potency if it has. been stored as
`directed.
`.
`‘
`Containers for Injections that are intended for use as dialysis,
`hemofiltration, or irrigation solutions and that contain a volume
`of more than 1 liter are labeled to indicate that the contents are
`not intended for use by intravenous infusion.
`Injections intended for veterinary use are labeled to that effect.
`The container is so. labeled that a sufficient area of the con-
`tainer remains uncovered for its full length or circumference to
`permit inspection of the contents.’
`'
`Packaging and Storage—The volume of Injection in single-dose
`containers provides the amount specified for parenteral admin-
`istration at one time and in no case is more than sufficient to
`permit the withdrawal and administration of 1 liter.
`Preparations intended for intraspinal, intracisternal, or peri-
`dural administration are packaged only in single-dose containers.
`Unless otherwise specified in the individual monograph, no
`multiple-dose container contains a volume of Injection more than
`sufficient to permit the withdrawal of 30 mL.
`‘
`Injections (packaged for use as irrigation solutions or for hemo-
`filtration or
`ialysis or for parenteral nutrition are exempt from
`the l-liter restriction of the foregoing requirements relating to
`packaging. Containers for Injections packaged for use as hemo-
`filtration or irrigation solutions may be designed to empty rapidly
`and may contain a volume of more than 1 liter.
`Injections labeled for veterinary use are exempt from pack—
`aging and storage requirements concerning the limitation to sin-
`gle-dose containers and the limitation on the volume of multiple-
`dose containers.
`
`CONSTITUTED SOLUTIONS‘
`Sterile dosage forms from which‘constituted solutions are pre-
`pared for injection bear titles of the form, Sterile _ or _
`for Injection. Since these dosage forms are constituted at the
`time of use by the health—care practitioner, tests and standards
`pertaining to the solution as constituted for administration are
`not included in the individual monographs on sterile dry solids
`or liquid concentrates. However, in the interest of assuring the
`quality of injection preparations as they are actually adminis-
`tered, the following nondestructive tests are provided for dem-
`onstrating the Suitability of constituted solutions when they are
`prepared just prior to use.
`'
`Completeness and Clarity of Solution—Constitute the solution
`as directed in the labeling supplied by the manufacturer for the
`sterile dry dosage form.
`,
`A: The solid dissolves completely, leaving no visible residue
`as undissolved matter.
`B: The constituted solution is not significantly less clear
`than an equal volume of the diluent or of Purified Water con-
`tained in a similar Vessel and examined similarly.
`
`Particulate Matter~Constitute the solution as directed in the
`labeling supplied by the manufacturer for the sterile dry dosage
`form:
`the solution is essentially free from particles of foreign
`matter that can be observed on visual inspection.
`
`(1 l) USP REFERENCE
`STANDARDS ‘
`USP Reference Standards are established and released under
`the authority of the USPC Board of Trustees upon recommen-
`dation of the USP Reference Standards Committee, which passes
`on the selection and suitability of each lot. The critical char-
`acteristics of each lot of specimen selected for the standard are
`usually determined independently in three or more laboratories.
`The USP Drug Researc and Testing Laboratory (see Preface)
`and the Food and Drug Administration laboratories participate
`in testing almost all new Standards and replacements for existing
`Standards. In addition, laboratories throughout the nation, both
`academic and industrial, participate in the testing.
`Reference Standards are specifically required in many Phar-
`macopeial assays and tests and are provided solely for such use;
`suitability for other non-official application(s) rests with the pur-
`chase. Originally introduced for the biological assays of USP X,
`reference standards are now required for numerous other pro-
`cedures as well. This reflects the extensive use of modern chro-
`matography and spectrophotometry, which require measurements
`relative to a reference standard to attain accurate and reprodu-
`cible results.
`USP Reference Standards are substances selected for their
`high purity, critical characteristics, and suitability for the in-
`tended purpose. Heterogeneous substances, of natural origin, also
`are designated “Reference Standards” where needed. Usually
`these are the counterparts of international standards.
`Antibiotic reference standards distributed by the USPC have
`been designated by the U.S. Food and Drug Administration as
`identical to FDA working standards under the FDA certification
`procedures. USPC distributes both US. Reference Standards
`and USP Reference Standards for antibiotic substances. This
`difference in labeling the Standards is in effect only temporaril ,
`and eventually all vials will bear the same title. Where a U P
`ReferenceStandard is called for, the corresponding substance
`labeled as a “US. Reference Standard" may be used, and vice
`versa.
`.
`_
`Reference Standards currently labeled as “NF Reference Stan-
`dards” will eventually all be designated and labeled as “USP
`Reference Standards’ pursuant to the consolidation of USP and
`NF within the USPC as of January 2, 1975. Meanwhile, where
`a USP Reference Standard is called for, the corresponding sub-
`stance labeled as an “NF Reference Standard" may be used.
`
`Other Reference Substances
`As a service, the USPC tests and distributes additional au-
`thenticated substances not currently required as USP or NF Ref-
`erence Standards. These also are provided under the supervision
`of the USP Reference Standards Committee. These additional
`substances fall into three groups:
`(1) former USP and NF Ref-
`erence Standards, not required in the current USP or NF but
`for which sufficient demand remains; (2) FCC Reference Stan-
`dards, specified in the current edition of the Food Chemicals
`Codex; and (3) Authentic Substances (AS), which are highly
`purified samples of chemicals, including substances of abuse, that
`are collaboratively tested and made available as a service PH-
`marily to analytical, clinical, pharmaceutical, and research lab-
`oratories.
`The distribution of controlled substances is subject to the reg'
`ulations and licensing provisions otthe Drug Enforcement Ad-
`ministration of the Department of Justice.
`As an additional service, the USPC distributes several non-
`commercial reagents required in certain USP monographs. These
`reagents are specially prepared for their intended use and will be
`a e.
`dliasltributed by USPC only until they become commercially avail-
`A program to provide international biological standards and
`chemical reference substances is maintained by the World Health
`Organization, an agency of the United Nations. The WHO pro-
`gram is concerned with reference materials for antibiotics,
`
`
`
`11*
`
` PFIZER, INC. v. NOVO NORDISK A/S - IPR2020-01252, Ex. 1068, p. 7 of 158
`
`

`

`USP XXII
`
`Apparatus / Automated Methods of Analysis
`
`(16)
`
`1473
`
`logicals, and chemotherapeutic agents. As a rule, an Interna-
`tional Standard for a material of natural origin is discontinued
`once the substance responsible for its characteristic activity has
`been isolated, identified, and prepared in such form that it can
`be completely characterized y chemical and physical means.
`The USP Reference Standards Committee collaborates closely
`with the WHO in order to minimize unavoidable differences in
`the actual units‘of potency, and in some cases to share in the
`preparation of a reference standard. Since some USP Reference
`tandards are standardized in terms of the corresponding Inter-
`national Standards, the relevant USP Units and the International
`Units of potency are generally identical.
`. Proper Use of USP Reference Standards—To serve its intended
`urpcse, each USP Reference Standard must bedprizperl
`stored,
`handled, and used. Generally, Reference Stan ar 5 sli'ould be
`stored in their original stoppered containers away from heat and
`protected from light. Avoid'humid storage areas in particular.
`Where special storage conditions are necessary, directions are
`given on the label.
`.
`Neither Reference Standards nor Authentic Substances are
`.intended for use as drugs or as medical devices.
`.-
`.
`_
`_.
`. Many Pharmacopeial tests and assays are based on comparison
`of a test specimen with a USP Reference Standard.
`In such
`cases, measurements are made on preparations of both the test
`specimen and the Reference Standard. Where it- is directed that
`a Standard solution or a Standard preparation, be prepared for
`a quantitative determination by stepwise dilution or otherwise, it
`is intended that the Reference Standard substance shall‘be ac-
`curately-weighed (see Weights and ,Balgmces (41) and Volu—
`metric Apparatus (31)). Due account should also be taken of
`the relatively large errors associated with weighing small masses
`(see also Dilut